Reply to: Oncogenesis in Patients With Pancreatic Intraductal Papillary Mucinous Neoplasms

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We would like to thank both the editors for the invitation and the authors for their response. As our colleagues pointed out, it is becoming increasingly evident that the immune response greatly influences the development and progression of pancreatic cancer.1 The immune system may, however, represent a “double-edged sword,” because different immune cell types have either tumor-inducing or tumor-suppressive potential.2 In our study on the predictive role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as markers of invasive malignancy in intraductal papillary mucinous neoplasms (IPMN), we attempted to gain a first insight on the inflammatory macroenvironment that may be present in patients with pancreatic premalignant lesions.3
It is well established that inflammation is a significant risk factor for carcinogenesis.4 In our retrospective study, none of the patients with IPMN-derived malignancies included in the final cohort had symptoms or clinical and imaging signs of acute pancreatitis within 30 days before surgery. Therefore, we were not able to assess the effect of an acute pancreatic inflammatory process on the immune response mechanism that could possibly be reflected through NLR and PLR. Regarding the presence of chronic inflammation in the pancreatic specimen, this was a diagnosis based on the final pathology report. In the univariate analysis, chronic pancreatitis in patients with IPMN-associated adenocarcinoma is significantly higher, but this does not remain a significant association on multivariate analysis. In addition, this being a clinical study, we did not assess the KRAS mutation status of the primary tumor. We suspect, however, that detection of KRAS mutations alone may not provide significant insight, because they seem to occur early in the development of IPMN, prior to progression into invasive malignancy and may be present even in low-grade dysplasia.5 In the future, a broader gene panel (GNAS, RNF43, DPC4, etc.) may be needed to determine any correlation between mutational status and immune response in IPMN.
One of the main reasons for the relatively small percentage of patients included in the final study cohort compared to all resected IPMN cases performed in our institution (39.9%) was the limited available preoperative differential blood work that provides absolute neutrophil and lymphocyte numbers for NLR and PLR calculation. We rereviewed the patients’ records; however, lymphocyte subset information was very limited and a detailed analysis of lymphocyte subtypes is not available for the present study. Regarding the amylase levels in the studied cohort, a review of the patients’ records did not show a statistically significant difference between benign IPMN and IPMN-associated invasive carcinoma. More specifically, median amylase value was 83, 78, and 85 U/L for groups 1, 2, and 3, respectively (P = 0.19). Data on lipase levels were very limited and could not be further assessed. Follow-up of both these pancreatic enzymes is included in our prospective study to determine their role in identifying IPMN malignant transformation. We would also like to thank the authors for their recommendation to assess additional immune response markers, such as the M30 and M65 antigens.
For the time being, we can say that there are indications that NLR and PLR may reflect the dynamic immunological response in patients with benign and malignant IPMN lesions, and may be of value as predictive markers for associated malignancy. This ability, however, appears to be limited when they are solely used; we believe that the substantial value of these inflammatory markers lies in their use as adjunct to the established consensus guidelines for the management of IPMN.

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